Migraine is a prevalent and disabling disorder that continues to confound best available medical therapy. An important obstacle to new more effective therapy is that we lack critical insights as to the relevant neurobiological targets. This is because the basic mechanisms contributing to this disorder remain elusive, and prevailing theories of the pathophysiology of migraine are based upon indirect or conflicting lines of evidence. Given what little direct evidence supports our understanding of migraine, any fundamental insight into the critical anti-migraine actions of sumatriptan action in the brain would be of great significance to our understanding of the disorder and the rational design of new therapies. The overall goal of this project is to elucidate the neurobiological actions of the migraine-specific drug sumatriptan. The inhibitory actions of sumatriptan in the periphery, on neurogenic inflammation and sensory neurons, are well described, but the mechanisms of sumatriptan in the brain remain virtually unexplored. This project focuses on the action of sumatriptan on pain-related circuits within the amygdala, and its influence on the affective-emotional processing of pain, through the activation of the 5HT1D receptor. Importantly, because a central clinical feature of migraine is the disturbance of the affective component of all sensory modalities, the modulation of the affective-emotional processing of pain by sumatriptan within the amygdala could potentially be a critical site for the anti-migraine activity of sumatriptan, and could be an important target for migraine therapy in the future. This applicant for a K02 Independent Scientist Career Development Award is a physician scientist with a longstanding commitment to a career in neuroscience research. This K02 award will support his continued career development and research that will lead to obtaining peer-reviewed, independent investigator-initiated funding. PUBLIC HEALTH RELEVANCE: Migraine is a common and disabling neurological disorder whose under-treatment is a major source of suffering, disability, and psychiatric comorbidity. Many Americans continue to suffer from migraine despite best medical treatment, and it remains the single most common neurological cause of disability and lost productivity in the United States. This project seeks to understand the mechanism of action of the foremost class of prescribed migraine-specific medication, sumatriptan, utilizing anatomical, molecular, and behavioral approaches to understanding its pain-modulatory actions, in hopes that it will yield important insights that will lead to new more effective therapy.